My research work largely explores the underlying physiologic questions regarding tiny vesicles called exosomes. These exosomes are released from many different types of cells or food-derived exosome-like nanoparticles and I am investigating in VA patients the promising role of exosomes as therapeutic vehicles in delivering treatment for a diverse but specific group of medical conditions, i.e.,obesity/diabetes, Nonalcoholic fatty liver disease (NASH), and cancer. There is a substantial population of veterans who are obese and/or have cancer. Obesity and cancer pose special burdens on veterans who depend on VA care. Obesity contributes to over 300,000 deaths per year and increases the risk of NASH, type 2 diabetes, and several cancers including colon, prostate, and kidney. Since receiving my initial Research Career Scientist award, my research group has published more than 50 manuscripts on this subject. Collectively, our findings support continued funding of my team to investigate the following 3 aims: (1) Tumor exosomes play a role in: (a) immunosuppression through induction of myeloid-derived suppressor cells, inhibition of dendritic cell differentiation, and inhibition of activation of NK cell immunotherapy; (b) by sorting suppressor miRNAs from tumor cells into exosomes based on the oncogenic major vault protein (MVP), tumors grow faster (Nature Communications. 2017 Feb 17;8:14448, Nature communications. 2015;6:6956); and (c) more recently, we discovered a novel nanoparticle (Oncotarget. 2016 May 12). Unlike other EVs, this extracellular nanovesicle (named HG-NV, HG-NV stands for HomoGenous nanovesicle as well as for Huang-Ge- nanovesicle) released from both mouse and human breast tumor cells is enriched with RNAs. Tumor-derived HG-NVs are more potent in promoting tumor progression than exosomes. Molecules predominantly present in breast tumor HG- NVs have been identified and characterized. This discovery may have implications in advancing both microvesicle biology research and clinical management including potential useas a biomarker, (2). Exosomes released from non-tumor cells play a role in: (a) adipose tissue exosome-like vesicles mediating activation of macrophage-induced insulin resistance (Diabetes. 2009 Nov;58(11):2498-505); (b) we also found that intestinal mucus-derived exosomes mediate activation of Wnt/?-catenin signaling and play a role in induction of liver NKT cell anergy (Hepatology, 2013 57(3):1250-61); and (c) intestinal mucus?derived exosomes carry prostaglandin E2 and suppress activation of liver NKT cells (J Immunol, 2013, 190(7):3579-89); (3). Exosome- like nanoparticles from edible plants have an effect and therapeutic application on mammalian cells: (a) we used mouse models to show that interspecies communication between plant and mouse gut host cells through edible plant derived exosome?like nanoparticles by inducing expression of genes for anti-inflammation cytokines, antioxidation, and activation of Wnt signaling, which are crucial for maintaining intestinal homeostasis. This finding not only opens up a new avenue for investigating ELNs as a means to protect against the development of liver related diseases such as alcohol induced liver damage, but sheds light on studying the cellular and molecular mechanisms underlying inter-species communication in the liver via edible plant- derived nanoparticles; (b) targeted drug/therapeutic miRNAs (Nature Communications. 2013;4:1867) delivery to intestinal macrophages, brain microglia cells (Molecular therapy: 2015, Volume 24, Issue 1, p96?105) and inflammatory tumor sites (Cancer Research, 2015;75:2520-9) by grapefruit ELN is possible; (c) Broccoli- Derived Nanoparticle Inhibits Mouse Colitis by Activating Dendritic Cell AMP-Activated Protein Kinase (Molecular Therapy. 2017, in press); and (d) Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis (Molecular Therapy. 2013 Jul;21(7):1345-57).